A review on the hybrids of hydroxycinnamic acid as multi-target-directed ligands against Alzheimer’s disease

Bioorganic & Medicinal Chemistry 26 (2018) 543–550

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Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc

Review article

A review on the hybrids of hydroxycinnamic acid as multi-targetdirected ligands against Alzheimer’s disease Xiao Zhang a,1, Xixin He b,⇑,1, Qiuhe Chen a, Junfeng Lu a, Simona Rapposelli c, Rongbiao Pi a,d,e,f,⇑ a

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China c Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy d International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong Province, Guangzhou 510006, China e Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China f National and Local United Engineering Lab of Drug Ability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510080, China b

a r t i c l e

i n f o

Article history: Received 8 November 2017 Revised 14 December 2017 Accepted 24 December 2017 Available online 26 December 2017 Keywords: Caffeic acid Ferulic acid Hybrids Multi-target-directed ligands Alzheimer’s disease

a b s t r a c t Alzheimer’s disease (AD), a complex chronic progressive central nervous system degenerative disease and a public health problem of the world, often characters cognitive dysfunction accompaning aggression and depression, and may lead to death. More attentions should be paid on it because there is no modified strategy against AD till now. AD is featured with the loss of cholinergic neurons, the amyloid-beta peptide (Ab) plaques and the neurofibrillary tangles and several hypotheses were established to explain the pathogenesis of AD. Hydroxycinnamic acids, including caffeic acid (CA) and ferulic acid (FA) are widely distributed in natural plants and fruits. CA and FA exert various pharmacological activities, including anti-inflammatory, antioxidant, neuroprotection, anti-amyloid aggregation and so on. All these pharmacological activities are associated with the treatment of AD. Here we summarized the pharmacological activities of CA and FA, and their hybrids as multi-target-directed ligands (MTDLs) against AD. The future application of CA and FA was also discussed, hoping to provide beneficial information for the development of CA- and FA-based MTDLs against AD. Ó 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacological effects of CA and FA for AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Inhibition of Ab aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Neuroprotection and oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Anti-inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hybrids of FA or CA for AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Dimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Rosmarinic acid derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Donepezil-related derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. With an amide bond bridge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. With an ester bond bridge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Tacrine-related derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. With none substitute alkyl linker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. With substitute alkyl linker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. The hybrids with NO donor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⇑ Corresponding authors at: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China (R. Pi). E-mail addresses: [email protected] (X. He), [email protected] (R. Pi). 1 Those authors contributed equally. https://doi.org/10.1016/j.bmc.2017.12.042 0968-0896/Ó 2017 Elsevier Ltd. All rights reserved.

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3.5. Rivastigmine-related derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Chalcone-related derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. The derivatives with Ab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. The derivatives with Carbazoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. The cinnamamide-N,N-dibenzyl (N-methyl) amine hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Prospect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

2. Pharmacological effects of CA and FA for AD

Alzheimer’s disease (AD), the most common age-related neurodegenerative disease, is a complex chronic progressive central nervous system (CNS) degenerative disease, which often leads to cognitive dysfunction, accompanied by aggression and depression, and may lead to death. The World Alzheimer Report 2016 said that there were about 50 million AD patients worldwide in 2016. The number is predicted to be more than 131 million by 2050 along with the aging of population.1 AD has become a giant challenge to the world because there is no effective disease-modified strategy for it till now. The pathogenesis of AD is complicated and not fully discovered till now. Many factors, including the deficiency of acetylcholine, the formation of neurotoxic beta-amyloid protein (Ab), tau protein hyperphosphorylation, metal ion disturbance, oxidative stress and so on, are involved in the process. Ab oligomer is a neurotoxic factor and recognized to play an important role in the pathogenesis of AD. Inhibiting the aggregation of Ab has been regarded as a promising strategy for AD. Moreover, mounting evidence demonstrated that the aggregation of Ab and metal ions dysfunction induce oxidative stress, which further leads to the loss of synaptic and the death of neuron. Thus, antioxidant may also be a promising useful strategy for AD. Many antioxidants were proved to exert beneficial effects in brain against the Ab-induced toxicity. Nevertheless, it is still a severe challenge to develop novel drugs for AD. The reasons mainly lie in the complexity and multi-factors of AD. Multi-target-directed ligands (MTDLs) is a concept raised up recently and means that the ligands could simultaneously affect multiple targets to realize multifunctional effects. Therefore, MTDLs, besides cholinesterase (ChE) inhibitors, are recognized as the new efficacious strategy to develop drugs for AD and attracted many labs.2–4 Hydroxycinnamic acid is a series of natural phenylpropenoic acid compounds, including caffeic acid (CA) and ferulic acid (FA), and widely distributed in vegetables and fruits5 as well as some Traditional Chinese Medicine, such as Ligusticum chuanxiong Hort. and Ferula sinkiangensis K.M. and so on.6 CA and FA have multiple pharmacological activities, including anti-inflammatory, antioxidant, neuroprotection, and anti-amyloid aggregation7, which are concerned with the treatment of AD.5,6,8 But there are still some shortcomings of CA or FA limiting their applications for AD, such as mild efficiency, low bioavailability and poor blood–brain barrier (BBB) penetration. Recently many labs and our lab have done wonderful jobs by using CA/FA as a core pharmacophore to develop MTDLs for AD. Here we reviewed the pharmacological activities of CA and FA, and their MTDLs-based derivatives developed recently for AD. The future application of CA and FA was also discussed, hoping to provide beneficial information for the development of CA and FA, and their MTDLs-based derivatives against AD.

2.1. Inhibition of Ab aggregation

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The amyloid cascade hypothesis is one of the important hypotheses of AD.9 Ab aggregation causes the deposition of amyloid fibrils, further leading to the formation of senile plaques (SP).10 The research suggests that the overproduction and deposition of Ab are pivotal pathogenic factors of AD. Ab results in the loss and toxicity of synapse, then damages neuron in the earlier stages of AD. Amyloid fibril is able to increase the formation of free radicals, and to induce oxidative stress in some cases.11 It was found that CA and FA had inhibitary activity on Ab aggregation. For example, Cui et al.12 reported that FA inhibited the transition of the Ab42 oligomer but accelerated the transition of Ab42 fibril. By using thioflavin T (ThT) fluorescence assay, Fourier transform infrared spectroscopy and size exclusion chromatography to study the interaction of FA and Ab40, Bramanti et al.13, found that FA inhibited Ab40 aggregation by interfering with self-assembly of peptides, and accelerated the formation of nonfibrillar aggregates. At the molecular level, these complexes had a beta structure, but they are more likely to be transformed into monomeric species. Although there is difference which may be related to the use of different Ab peptide, these results revealed the effects of FA on Ab. 2.2. Neuroprotection and oxidative stress FA has neuroprotective and neurotropic effects when was administrated by the parenteral route for a short term. FA is found to attenuate brain injury induced by deprivation of reduced glutathione and had significantly increased the cognitive activity in mice. In addition, Cui et al.12 also found that FA significantly reduced the cell death induced by Ab42 in SH-SY5Y cells. Kim et al.14 found CA possessed good protective abilities, and promoted cognitive and memory functions in Ab25-35-induced AD mice. Meanwhile, CA reduced the lipid peroxidation and nitric oxide (NO) formation in the liver, kidney, and brain of these mice. Moreover, FA (150 mg/kg i.p.) was reported to exert strong neuroprotective effects by reducing Ab-induced reactive oxygen species (ROS) and reactive nitrogen species and up-regulating both heme oxygenase 1 and heat shock protein 70, two neuroprotective factors in gerbil brain synaptosomes.15 2.3. Anti-inflammation The levels of interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), two important markers of inflammation, are increased in AD patients. CA significantly reduced the levels of IL-6 and TNF-a which were increased in the AD patients.16 In aged rats (21 months), dietary supplementation with sodium ferulate for 4 weeks had counteracted the increase, induced by pro-inflammatory

X. Zhang et al. / Bioorganic & Medicinal Chemistry 26 (2018) 543–550

cytokines, such as interleukin-1b (IL-1b) and has contributed to preventing the reduction of the activity of proteins, such as extracellular regulated protein kinases and pro-to-oncogene protein kinase B.8 Yan et al.17 found that the production of IL-1b was decreased by treating with FA for 4 weeks. Meanwhile, FA counteracted the neuroinflammation and gliosis in the mouse brain induced by injecting Ab and improved memory loss as well. 3. Hybrids of FA or CA for AD 3.1. Dimer

545

8.71 ± 0.20; FA, 3.74; melatonin, 2.45). It was also a potent selective butyrylcholinesterase (BuChE) inhibitor (10.39 ± 0.48 nM). Sang et al.26 designed and synthesized a new series of FA-Oalkylamines derivatives. Among these compounds, compound 6 was the most potent BuChE inhibitor (IC50 = 0.021 mM, 8.63 mM and 0.07 mM for equine serum BuChE, rat BuChE and hBuChE, respectively) with a low activity against AChE (IC50 = 3.82 mM for hAChE). Moreover, compound 6 not only inhibited the self-induced Ab1-42 aggregation (50.8 ± 0.82%), but also disaggregated selfinduced Ab1-42 aggregation (38.7 ± 0.65%). In addition, compound 6 also has mild antioxidant activity (0.55 eq of Trolox) and potently protects PC12 cells against H2O2-induced cell injury with low toxicity. Estrada M. et al.27 reported a new series of hybrids by linking antioxidant cinnamic-related structures with NBP fragments. These hybrids had antioxidant, neuroprotective properties against mitochondrial oxidative stress, and ChE inhibitory and monoamine oxidases (hMAO-A and hMAO-B). The representative caffeic-NBP hybrid 7 displayed good activities with IC50 in the low-micromolar and submicromolar range against hChEs and hMAOs respectively, and an antioxidant potency equaling to vitamin E. It is interesting that 7 also differentiated adult SGZ-derived neural stem cells into neurons in vitro.

Oligomer of Ab is the most toxic type and is produced through aggregation. Oligomers would produce fibril and become SP, one of the main pathological characteristics of AD. The overproduction and aggregation of Ab were important pathogenic factors for AD and aggregated-Ab induced oxidative stress. It should be important to find a drug with anti-Ab-aggregation inhibitory and antioxidant effects. Cinnamic acid is a good pharmacophore to develop agents against Ab aggregation with ROS scavenging ability.18 Our group synthesized a series of novel FA and CA dimers linked with diamine. Their pharmacological activities against AD were evaluated by thioflavin T (Th-T), DPPH scavenging and MTT assays. Those compounds possessed good inhibitors against acetylcholinesterase (AChE)-induced and self- Ab1–42 aggregation.19 Dimeric hybrid 1 with a benzidinyl linker had potent neuroprotection against glutamate-induced cell death in HT22 cells and potent inhibition of Ab1–42 aggregation at 10 lM (83.7%). A ferulic dimer linked with a CAC bond, named KMS4001 (2) was synthesized and evaluated in vivo.20 The compound 2 could significantly improve the cognitive ability damaged by the Ab1-42 (i.c.v.) in both Y-maze and passive avoidance tests, and also significantly enhance novel-object recognition memory and decrease Ab1-40 and Ab1-42 levels in APP/PS1 transgenic AD mice.

3.3.2. With an ester bond bridge Recently, Dias K et al.28 synthesized and evaluated a novel series of feruloyl-donepezil hybrids as MTDLs for AD by ester bond bridge. In vitro results revealed all of them exerted moderate antioxidant properties, and some of them exhibited potent AChE inhibitory activity. Hybrid 8 had not only the most potent AChE inhibitors (IC50 0.46 lM), significant in vivo anti-inflammatory activity in diversity models in the mice, such as paw edema, pleurisy and formalin-induced hyperalgesia, but also in vitro metal chelator activity for Cu2+ and Fe2+, and neuroprotection of human neuronal cells against oxidative damage.

3.2. Rosmarinic acid derivatives

3.4. Tacrine-related derivatives

Rosmarinic acid, a natural ferulic derivative, is reported to show a high antioxidant activity. Ab-induced neuronal toxicity is mediated by ROS that induces subsequent Ab aggregation and speeds up the AD progression21 and antioxidants with catechol moiety showed to inhibit Ab aggregation.22 Taguchi et al.23 reported a series of novel rosmarinic acid derivatives with anti-aggregation, antioxidant and also xanthine oxidase inhibition. Among these compounds, compounds 3 and 4 were found to be the most potent Ab aggregation inhibitors. The structure-activity relationship study revealed that the phenolic hydroxyl on one side of the molecule as well as the lipophilicity are very important.

3.4.1. With none substitute alkyl linker Tacrine, the first marketed ChE inhibitor for the treatment of AD, has favorable inhibitory activities of AChE and BuChE. However, due to its hepatotoxicity and peripheral side effects, tacrine was almost withdrawn from the pharmaceutical market. But the research of tacrine has never been abandoned. Our group synthesized a series of FA-tacrine derivatives as multifunctional agents.29 Among of them, hybrid 9 effectively inhibited Ab1–40 aggregation in vitro and protected cells from the injury induced by Ab1–40 in PC12 cells. Meanwhile, 9 increased the levels of choline acetyltransferase (ChAT) and superoxide dismutase (SOD). The levels of AChE and malondialdehyde (MDA) were decreased by treating with 9 in an AD mouse. Moreover, our group also found that 10 protected HT22 cells against cell death induced by glutamate and potently scavenged intracellular ROS.30 Compound 10 protected neurons against the injury induced by ROS, which was found 10 worked by Nrf2/ARE/HO-1 signaling pathway.

3.3. Donepezil-related derivatives Acetylcholine deficiency is a key pathogenesis in AD. Current marketed drugs for AD mainly targeted ChE system. Donepezil, a clinic used AChE inhibitor, is the second ChE inhibitor approved by FDA (US) for AD. In donepezil, N-benzylpiperidine moiety had been proven to be an necessary structure for ChE inhibition and has been used for the design of MTDLs.24 3.3.1. With an amide bond bridge By an amide bond bridge, FA was conjugated with N-benzylpiperidine(NBP) to generate a series of novel compounds with the effects of inhibiting ChE and preventing oxidation.25 Compound 5, a multi-target drug, showed good antioxidant activities, more effective than FA or melatonin (ORAC value: compound 5,

3.4.2. With substitute alkyl linker With an alkyl linker, tacrine can be dimered with other pharmacophore to generate MTDLs. A series of tacrine-FA hybrids were synthesized by a alkyl linker.31 Among them, hybrid 11 exerted the high selective AChE inhibition, potent inhibition of Ab selfaggregation, copper chelation and neuroprotection against the Ab-induced toxicity. Digiacomo et al.32 conjugated tacrine and FA (or CA) by the 2-hydroxypropil chain to generate a series of compounds with good antioxidant capacities. Among of these compounds, 12 also showed a good ability to inhibit the

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Ab self-aggregation (53.2% at 50 lM), AChE and BuChE inhibitory (AChE, IC50 = 0.15 lM; BuChE, IC50 = 0.36 lM), modest BACE1 inhibitory (13.07 ± 5.81% at 10 lM). Furthermore, the antioxidant and neuroprotective effects were detected by DPPH scavenging assay and MTT assay. The results showed that 12 had 90.36 ± 1.40% of DPPH scavenging ability at 10 lM and significant neuroprotection against glutamate-induced cell death in HT22 cells at 10 lM. Benchekroun et al.33 designed and synthesized some novel multifunctional FA derivatives. The derivatives contain three pharmacophores (FA, tarcrine and melatonin). Compound 13 exhibited excellent antioxidant and neuroprotective activities, potent ChE inhibition and low hepatotoxicity. It was regarded as a promising agent in the treatment of AD. 3.4.3. The hybrids with NO donor NO, a multifunctional messenger molecule, was confirmed that it has many physiological functions such as vasodilatation, immune response and enhancement of synaptic transmission.34 It was found that NO may be useful for the treatment of AD, which may work through increasing blood flow and supply to the brain. In recent years, the NO-donating compound strategy was studied in the treatment of AD, and had been proven to be effective.35 Zhang et al.36 synthesized a series of tacrine-FA-NO donor trihybrids, which had more effective ChE inhibition than tacrine in vitro. Compound 14 had vasodilation effect in vitro, which may relate with the NO released by NO donor. In addition, it also improved cognitive function in AD mice model induced by scopolamine, and was less hepatotoxicity than tacrine. 3.5. Rivastigmine-related derivatives Rivastigmine, the marketed irreversible ChE inhibitor, is the only drug used to treat severe AD.37 Our group reported a series of rivastigmine-CA and rivastigmine-FA hybrids, and evaluated multifunctional agents in vitro.38 The new compounds showed good antioxidant and neuroprotective properties, and also had good ChE and Ab aggregation inhibitory activities. Among these compounds, 15 exerted 51.7% of DPPH scavenging ability at 10 lM, neuroprotective property on HT22 cells against cell injury induced by glutamate and H2O2 at 10 lM, ChE inhibitory (AChE 23.42% at 1 lM; BuChE 76.32% at 1 lM), the best Ab self-aggregation inhibitory (85.3% at 10 lM) and copper chelation properties. All these activities should be benefit for AD. 3.6. Chalcone-related derivatives Chalcone, a special natural product containing a, b-unsaturatedcarbonyl group, is considered as an ideal structure to design multifunctional compounds by structure modification. The structures of many AChE inhibitors found in natural plant are similar to the structure of chalcone. These AChE inhibitors may be new resources for further developing MTDLs-based anti-AD agents. Liu et al.39 designed and synthesized a series of FA-chalcone derivatives and the AChE inhibitory activities of most of FA-chalcone derivatives were stronger than that of rivastigmine. The linker between tertiary amine groups and FA scaffold is critical to the AChE inhibition. The AChE inhibition of 16 was over 10 times stronger than that of rivastigmine (IC50: 16, 0.71 ± 0.09 mM; rivastigmine, 10.54 ± 0.86 mM). 3.7. The derivatives with Ab Increased Ab deposition and oxidative stress observed in the AD brain are recognized as useful targets for therapeutic intervention. Using similar fragment of Ab to bind and then inhibit the Ab aggre-

gation is a novel and good strategy for AD.40 Arai et al.40 conjugated the antioxidant CA and dihydrocaffeic acid (DHCA) to Ab1–42Cterminal motifs (Abx–42: x = 38, 40) to synthesize CA-Abx–42 and DHCA-Abx–42, respectively. Among the compounds, CA-Ab38–42 17 exhibited potent inhibitory activity against Ab1–42 aggregation and scavenged Ab1–42-induced intracellular oxidative stress. Moreover, CA-Ab38–42 significantly protected SH-SY5Y cells from Ab1–42-induced cytotoxicity with IC50 of 4 lM. Above results suggest that CA-Ab38–42 17 might be a promising candidate for AD. 3.8. The derivatives with Carbazoles Carbazole moiety is a multifunctional scaffold with a variety of biological applications, for example, neuroprotection and carbazole derivatives could inhibit the aggregation of Ab.41,42 2,8-Disubstituted carbazole derivatives, could inhibit ChE and protect neurons from the toxicity induced by Ab oligomers.43 Taking advantage of carbazole and FA scaffolds, Fang L. et al.44 synthesized a series of FA-Carbazole hybrids. Among them, compound 18 exhibited multifunctional effects, including potency AChE inhibition (IC50 1.9 lM), pronounced antioxidant ability and significant neuroprotection against the ROS-induced damage, being obviously better than that of the combination of FA and carbazole. 3.9. The cinnamamide-N,N-dibenzyl (N-methyl) amine hybrids Basing on the dual binding theory, hAChE has two sites, the catalytic and the peripheral binding sites and the peripheral binding sites of AChE has Ab pro-aggregating activities.45 AP2238 was a potent AChE inhibitor that can bind simultaneously with both the catalytic and the peripheral binding sites of hAChE. It also potently inhibited AChE-induced Ab aggregation.46 A novel series of hybrids with a moiety of AP2238 and cinnamamide have been synthesized and bio-evaluated.47 Most of the target compounds exhibited potent inhibitory of Ab self-aggregation, significant inhibitory of ChEs, and performed as antioxidants and biometal chelators. Especially, compound 19 bind with both the catalytic anionic site and peripheral anionic site of AChE, chelated metal ions, reduced PC12 cells death induced by oxidative stress and penetrate BBB, and could be a promising candidate for AD, which is worthy of further investigation. Similarly, another series of Ferulic-DBMA [N,N-dibenzyl(Nmethyl) amine (DBMA)] were synthesized and bio-evaluated their effects of antioxidant, neuroprotection against oxidative stress, and inhibitory against cholinesterases (hAChE and hBuChE) and monoamine oxidases activities.27 The representative hybrid 20 displayed good inhibitory activities against hChEs and hMAOs with IC50 in the low-micromolar and submicromolar range respectively, and also good antioxidative activity. 3.10. Others Quaternary ammonium is a kind of ChE inhibitor. The dual-targeting cinnamic acid-quaternary ammonium ligands have been developed and in vitro evaluated their biological activities. FA-quaternary ammonium hybrid 21 showed a weak AChE inhibitory activity at micromolar range, good antioxidant properties and neuroprotective efforts.48 Isosorbide-2-carbamates-5-aryl esters are highly selective inhibitors against BuChE. The ferulic acid hybrid 22 was synthesized by replaced the isosorbide-aryl-5-ester group with FA and had antioxidation and potenter inhibitory activity against BuChE over AChE.49 No toxic effects were observed when the hybrid 22 was exposed to HT22 cells, a murine hippocampal cell line.

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X. Zhang et al. / Bioorganic & Medicinal Chemistry 26 (2018) 543–550 Table 1 The hybrids of Cafferic acid or Ferulic acid and their biological effects for the treatment of AD. Entry

Structure

Hybrid type

Main biological efforts

References

1

Dimer (With a benzidinyl linker)

Ab1–42 aggregation and self-induced aggregation inhibitor, antioxidant, potent neuroprotector

19

2

Dimer (linked with CAC bond)

Significantly attenuate the Ab1-42 (i.c.v.)inducedmemory impairment, enhance novel-object recognition memory and decrease Ab1-40 and Ab1-42 levels in APP/PS1 mutant transgenic mice.

20

3 and 4

Rosmarinic acid derivatives

Amyloidaggregation inhibitor

23

5

Donepezil-related (With an amide bond bridge)

Antioxidant, selective BuChE inhibitor

25

6

Donepezil-related (With an amide bond bridge)

Antioxidant, selective BuChE inhibitor, neuroprotector, anti-self-induced Ab1-42 aggregation

26

7

Donepezil-related (With an amide bond bridge)

Low-micro and submicromolar range for hChEs and hMAOs, antioxidant and neuroprotective properties, improving adult SGZ-derived neural stem cells into a neuronal phenotype in vitro.

27

8

Donepezil-related (With an ester bond bridge)

Antioxidant, ChE inhibitor, neuroprotector, antiinflammation, metal chelator

28

9

Tacrine-related (with none substitute alkyl linker)

Neuroprotector, self- and AChE-induced aggregation inhibitor, improving cognition

29

(continued on next page)

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X. Zhang et al. / Bioorganic & Medicinal Chemistry 26 (2018) 543–550

Table 1 (continued) Entry

Hybrid type

Main biological efforts

References

10

Structure

Tacrine-related (with none substitute alkyl linker)

Neuroprotector, attenuated intracellular ROS production

30

11

Tacrine-related (with substitute alkyl linker)

Selective AChE inhibitor, self-Ab aggregation inhibitor, chelating Cu2+, neuroprotector

31

12

Tacrine-related (with substitute alkyl linker)

Neuroprotector, AChE and BuChE inhibitors, antioxidant, Ab-induced aggregation inhibitor

32

13

Tacrine-related (with substitute alkyl linker)

Antioxidant, strong ChE inhibitory activity, less hepatotoxicity, neuroprotector

33

14

Tacrine-related (With NO donor)

ChE inhibitor, moderate vasorelaxation, less hepatotoxicity, improving cognition

36

15

Rivastigmine related

Antioxidant, neuroprotective properties, ChE and Ab aggregation inhibitory activities, copper chelation

38

16

Chalcone-related

Potent AChE inhibitory activity

39

17

Link Abx-42

Neuroblastoma SH-SY5Y protector, scavenged intracellular oxidative stress, Ab1–42 aggregation inhibitor

40

18

Carbazoles related

Potent ChE inhibitor, antioxidant, neuroprotector

44

19 and 20

N,N-dibenzyl(N-methyl) amine related

Potent ChE inhibitor, antioxidant, neuroprotector, biometal chelators, anti-Ab aggregation, penetrate the blood brain barrier (BBB) (19) Low-micro and submicromolar range for hChEs and hMAOs, antioxidant and neuroprotective properties (20)

19 Ref.47 20 Ref.24

549

X. Zhang et al. / Bioorganic & Medicinal Chemistry 26 (2018) 543–550 Table 1 (continued) Entry

Hybrid type

Main biological efforts

References

21

Structure

Link a quaternary ammonium

A weak AChE inhibitory activity, good antioxidant and neuroprotective efforts

48

22

Isosorbide-based phenyl carbamates

Potent inhibitory against BuChE over AChE, good antioxidation

49

4. Prospect In the review, a series of FA/CA-based MTDLs for AD were firstly summarized (see also Table 1). They are multifunctional, including ChE inhibitory, copper chelatory, vasorelaxation, neuroprotection, anti-inflammation, and anti-Ab aggregation. FA and CA are two multifunctional natural hydroxycinnamic acids with antioxidant, neuroprotective, anti-inflammatory and inhibitory effects of Ab aggregation, while the activity is not so strong. Their structures are simple and their antioxidative activity derives from its 4-phenolic hydroxyl and ethylenic bond. FA and CA are widespread in many plants and are easy to be gotten. They are selected for structural modification for their small molecular weights and multiple functions though of their some poor BBB penetration. Taking account of the complexity of the pathogenesis of AD, single-target drug cannot modify the disease and MTDLs are recognized gradually to be the most promising strategy.3 Basing on the advantages and disadvantages of FA and CA, AD might be tamed by using FA or CA as a pharmacophore to develop single-molecule-multi-target drugs. In addition, CA/FA also can be conjugated with some pharmacophore(s) targeting for other targets involving in AD to achieve multi-targeted therapy. The BBB penetration of drug candidate(s) derived from CA/FA would be improved at the same time. Given that the 4-phenolic hydroxyl and ethylenic bond are important for the activities of CA/FA, and they should be retained in further modification. More and more novel targets were discovered for AD. Rational design of MTDLs to these novel targets should also be very interesting. Recent studies demonstrated that epigenetic mechanisms played important roles in AD pathology and modulating histone acetylation was a promising strategy for the therapy of AD. Increasing evidence showed that inhibitors of histone deacetylase should be novel promising therapeutic agents for AD.50 FA/CA is easy to design and modified into HDACs inhibitors.51 Development of MTDLs-based FA/CA hybrids with histone deacetylase inhibitory should be an interesting field of R&D drugs for AD in the future. In summary, FA and CA are simple structures with multi-target activities, and should be useful to develop MTDLs for AD.

Conflict of interest The authors declare that there is no interest conflict.

Acknowledgments This work were supported by grants from Guangdong Provincial International Cooperation Project of Science & Technology (No 2013B051000038), national natural scientific foundation

committee (No 31371070) to R. Pi. And all authors also thanks to Dr. Myaen Yein Chan for her the wonderful proofread job.

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